PROJECT SUMMARY Neurodegenerative diseases are debilitating for patients and their families, and are becoming a health epidemic. Many of these patients suffer from memory loss and disruptions in learning, language, behavior and motor coordination. The current standard of care for neurodegenerative disease remains palliative, as there are no methods to prevent or cure them. Many neurodegenerative diseases are classified as tauopathies. Tauopathies are an irreversible, progressive disease caused by massive neuronal cell death, and characterized by aberrant aggregation of tau protein. Although it is known that tau aggregation is a major characteristic of neurodegeneration, the molecular mechanisms involved in the etiology remains unknown. Investigators have developed a transgenic mouse expressing a mutated form of human tau protein (P301S) that is prone to aggregation. Like human patients, P301S mice develop tau aggregates and neuronal cell death. Surprisingly, a mouse model with a deletion in a chromatin-modifying enzyme, LSD1, recapitulates the tauopathy neurodegenerative phenotype. LSD1 was shown to be required for neuron survival. In human cases, LSD1 specifically co-localizes with tau aggregates. Our data suggest a model where pathological tau aggregates sequester LSD1 in the cytoplasm, interfering with LSD1 function, and leading to neural cell death. To investigate the role of LSD1 in tau-mediated neurodegeneration, we generated a mouse with the P301S transgene that is heterozygous for Lsd1 (P301S;LSD1?/+). We hypothesize that if the defects observed in P301S mice are due in part to LSD1 sequestration, then reducing LSD1 levels may accelerate the tauopathy phenotypes. My data show that this allelic combination results in a synergistic effect on survival, rate of paralysis, and neruodegeneration in the brain and spinal cord. In this proposal, we will take genetic and biochemical approaches to investigate the interaction between LSD1 and tau. In specific Aim 1, we will characterize the interaction of LSD1 and tau throughout disease progression in the P301;Lsd1?/+ compared to the P301S mouse. We will perform behavioral, physiological, and pathological assays at several time points indicative of tau pathological progression in the brain and spinal cord. We will also test whether increasing the levels of LSD1 expression can overcome tau-mediated neurodegeneration. For this, we will express LSD1 specifically in hippocampal neurons of the P301S mouse. Specific Aim 2 will take a biochemical approach to investigate the molecular interaction between LSD1 and tau in disease. We will test if there is an in vivo interaction between LSD1 and tau through a series of co-immunoprecipitations in P301S mice and human affected cases. We will also test our sequestration model by comparing LSD1 cytoplasmic-to-nuclear localization through tau aggregate progression. The aims in this proposal will investigate a novel interaction for tau, and the outcomes will have a significant impact on the role of pathological tau in tauopathy etiology. The long-term goal of these studies is to identify targetable pathways to inhibit tau-mediated neurodegeneration.